Showing posts with label genotypes;All. Show all posts
Showing posts with label genotypes;All. Show all posts

Tuesday, December 4, 2018

China's National Medical Products Administration Approves Harvoni®

China’s National Medical Products Administration Approves Harvoni® (Ledipasvir/Sofosbuvir) for Treatment of Chronic Hepatitis C Virus Genotype 1-6

--Harvoni Offers Highly Effective, Short-Duration, Pan-Genotypic Treatment for Chinese Patients with HCV Infection--

--Harvoni Achieved Cure Rate (SVR12) of 100 Percent in Clinical Trial of Chinese Patients with Genotype 1--

FOSTER CITY, Calif.--(BUSINESS WIRE)--Dec. 4, 2018-- Gilead Sciences, Inc. (NASDAQ: GILD) announced today that the National Medical Products Administration (NMPA) has approved Harvoni® (ledipasvir 90 mg/sofosbuvir 400 mg) in China for the treatment of chronic hepatitis C virus (HCV) genotype 1-6 infection in adults and adolescents aged 12 to 18 years.

Hepatitis C is a significant public health challenge. Nearly 10 million people in China are estimated to have chronic HCV, with approximately 58 percent having HCV genotype 1 infection.

“The multicenter clinical trials in China have shown that the once-daily single tablet treatment regimen of Harvoni achieved a 100% SVR12 (defined as undetectable HCV RNA 12 weeks after completing therapy) rate in treatment patients with genotype 1 HCV infection,” said Professor Lai Wei, Peking University People’s Hospital and Institute of Hepatology, Beijing.

“Gilead has continued to develop and deliver new treatments for HCV to help enable people with HCV the potential to be cured,” said John McHutchison, AO, MD, Chief Scientific Officer, Head of Research and Development, Gilead Sciences. “We are pleased to offer an important new treatment option that can help patients achieve HCV cure and further support efforts to stem the epidemic in China.”

The approval of Harvoni in China is supported by an open-label, Phase 3b study, which was conducted at 18 study centers in mainland China between May 2016 and July 2017. The study evaluated 12 weeks of treatment with Harvoni in 206 genotype 1 HCV patients, including treatment-naïve and treatment-experienced patients without cirrhosis or with compensated cirrhosis.

Saturday, November 3, 2018

Minireview - Era of direct acting anti-viral agents for the treatment of hepatitis C

World J Hepatol. Oct 27, 2018; 10(10): 670-684
Published online Oct 27, 2018. doi: 10.4254/wjh.v10.i10.670

The different DAAs with their dose, efficacy, side effects, drug-drug interactions as well as specific treatment against different genotypes of HCV will be discussed.

Minireview
Era of direct acting anti-viral agents for the treatment of hepatitis C 
Monjur Ahmed 

Core Tip: Treatment of hepatitis C has now become much easy and simple with the advent of direct acting anti-viral agents (DAAs) against hepatitis C virus (HCV). Although the DAAs are highly effective in eradicating HCV infection, they have different mechanisms of action, side effects, resistance factors and drug-drug interactions. The treatment also varies in special situations like HCV/ human immunodeficiency virus co-infection and post-liver transplant patients. Physicians treating patients with HCV infection should have a clear knowledge about the DAAs as well as the current guidelines.

Read the complete article online
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New highly diverse hepatitis C strains detected in sub‐Saharan Africa have unknown susceptibility to direct‐acting antiviral treatments

New highly diverse hepatitis C strains detected in sub‐Saharan Africa have unknown susceptibility to direct‐acting antiviral treatments 
Chris Davis George S. Mgomella Ana da Silva Filipe Eric H. Frost Genevieve Giroux Joseph Hughes Catherine Hogan Pontiano Kaleebu Gershim Asiki John McLauchlan Marc Niebel

 First published: 02 November 2018
https://doi.org/10.1002/hep.30342 

Full-Text Article
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Accepted manuscript online: This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record.

Abstract
Background and rationale for the study
The global plan to eradicate hepatitis C (HCV) led by the World Health Organisation (WHO) outlines the use of highly effective direct‐acting antiviral drugs (DAAs) to achieve elimination by 2030. Identifying individuals with active disease and investigation of the breadth of diversity of the virus sub‐Saharan Africa (SSA) is essential as genotypes in this region (where very few clinical trials have been carried out) are distinct from those found in other parts of the world. We undertook a population‐based nested case‐control study in Uganda and obtained additional samples from the Democratic Republic of Congo (DRC), to estimate the prevalence of HCV, assess strategies for disease detection using serological and molecular techniques, and characterise genetic diversity of the virus. Using next generation (NGS) and Sanger sequencing, we aimed to identify strains circulating in East and Central Africa.

Main results
7751 Ugandan patients were initially screened for HCV and 20 PCR positive samples obtained for sequencing. Serological assays were found to vary significantly in specificity for HCV. HCV strains detected in Uganda included genotypes (g) 4k, 4p, 4q and 4s and a new unassigned genotype 7 HCV strain. Two additional unassigned g7 strains were identified in patients originating from DRC (one partial and one full ORF sequence). These g4 and 7 strains contain NS3 and NS5A polymorphisms associated with resistance to DAAs in other genotypes. Clinical studies are therefore indicated to investigate treatment response in infected patients.

Conclusion
While HCV prevalence and genotypes have been well characterised in patients in well‐resourced countries, clinical trials are urgently required in SSA where highly diverse g4 and 7 strains circulate.

Thursday, September 20, 2018

Ultra-Short Treatment of Hepatitis C - Cocrystal Pharma Completes Patient Enrollment in Phase 2a Study Evaluating CC-31244

ATLANTA, GA and BOTHELL, WA, Sept. 20, 2018 (GLOBE NEWSWIRE) -- Cocrystal Pharma, Inc. (NASDAQ: COCP), (“Cocrystal” or the “Company”), a clinical stage biotechnology company discovering and developing novel antiviral therapeutics that target the replication machinery of hepatitis viruses, influenza viruses and noroviruses, announced today the completion of patient enrollment in its Phase 2a clinical study evaluating CC-31244 for the ultra-short treatment of hepatitis C virus (HCV)-infected individuals.

CC-31244, the Company’s lead product in development for hepatitis C (HepC), is an investigational, oral, potent, broad-spectrum replication inhibitor called a non-nucleoside inhibitor (NNI). It has a high barrier to drug resistance designed and developed using the Company's proprietary structure-based drug discovery technology. It is active against HCV genotypes 1-6 with no significant cytotoxicity in multiple cell types at high concentrations.

“A major focus this year for Cocrystal has been the execution of our Phase 2a HepC study with our lead program CC-31224 combined with Epclusa. The on-time completion of patient enrollment marks a significant milestone for the Company and a testament to the focus as well as the expertise of our clinical team,” commented Gary Wilcox, Ph.D., Vice Chairman and Chief Executive Officer of Cocrystal. “We are pleased that there were no serious adverse events observed and that the combination was well tolerated in all patients. We now look forward to the completion of patient dosing and announcement of initial results in Q4.”

The Phase 2a open-label study is designed to evaluate the safety, tolerability and preliminary efficacy of CC-31244 with Gilead Science’s Epclusa®. Enrolled subjects self-administer orally 400 mg of CC-31244 and a fixed dose of Epclusa for 14 days. After 14 days the subjects continue the treatment for another four weeks on Epclusa alone. Primary and secondary efficacy endpoints are sustained virologic response (SVR) at 12 weeks post-treatment (SVR12) and at 24 weeks post-treatment (SVR24), respectively.

Joel Chua, M.D., Assistant Professor of Medicine and Principal Investigator of the Phase 2a study Institute of Human Virology at the University of Maryland School of Medicine, commented, “I am pleased with the progression of the Phase 2a study of CC-31244 and believe it has significant potential to address the need for treatment options with ultra-short duration for individuals chronically infected with hepatitis C.”

For additional information about the Phase 2a study of CC-31244 for the treatment of viral hepatitis C, please visit ClinicalTrials.gov and reference identifier NCT03501550.

About CC-31244
CC-31244 is an investigational, oral, broad-spectrum replication inhibitor called a non-nucleoside inhibitor (NNI). It has been designed and developed using the Company's proprietary structure-based drug discovery technology to have a high barrier to drug resistance and to be a highly potent, selective NNI that is active against all HCV genotypes (1-6) with low level cytotoxicity in multiple cell types.

About Hepatitis C
Hepatitis C is a viral infection of the liver that causes both acute and chronic infection, and according to the World Health Organization in 2017, affects an estimated 71 million people worldwide, including 3.5 million in the United States. Chronic hepatitis C virus infection can lead to fibrosis (scarring), cirrhosis, liver failure, and liver cancer. Approximately 399,000 people die each year from hepatitis C, mostly from cirrhosis and hepatocellular carcinoma.

Wednesday, June 13, 2018

High SVR12 with 8-week and 12-week glecaprevir/pibrentasvir therapy: An integrated analysis of HCV genotype 1–6 patients without cirrhosis

High SVR12 with 8-week and 12-week glecaprevir/pibrentasvir therapy: An integrated analysis of HCV genotype 1–6 patients without cirrhosis


Open Access

Highlights
•A short-duration, pangenotypic cure for HCV infection may help treat more patients.
•Glecaprevir plus pibrentasvir (G/P) therapy for 8 weeks had an overall cure rate of 98%.
•The efficacy of 12-week G/P therapy (99%) was not significantly higher than that of 8-week G/P therapy (p = 0.2).
•Treatment responses were high irrespective of any baseline patient or viral trait.
•G/P demonstrated a favourable safety profile regardless of treatment duration.

Background & Aims
Glecaprevir plus pibrentasvir (G/P) is a pangenotypic, once-daily, ribavirin-free direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection. In nine phase II or III clinical trials, G/P therapy achieved rates of sustained virologic response 12 weeks after treatment (SVR12) of 93–100% across all six major HCV genotypes (GTs). An integrated efficacy analysis of 8- and 12-week G/P therapy in patients without cirrhosis with HCV GT 1–6 infection was performed.

Methods
Data were pooled from nine phase II and III trials including patients with chronic HCV GT 1–6 infection without cirrhosis who received G/P (300 mg/120 mg) for either 8 or 12 weeks. Patients were treatment naïve or treatment experienced with peginterferon, ribavirin, and/or sofosbuvir; all patients infected with HCV GT 3 were treatment naïve. Efficacy was evaluated as the SVR12 rate.

Results
The analysis included 2,041 patients without cirrhosis. In the intent-to-treat population, 943/965 patients (98%) achieved SVR12 when treated for eight weeks, and 1,060/1,076 patients (99%) achieved SVR12 when treated for 12 weeks; the difference in rates was not significant (p = 0.2). A subgroup analysis demonstrated SVR12 rates > 95% across baseline factors traditionally associated with lower efficacy. G/P was well tolerated, with one DAA-related serious adverse event (<0.1%); grade 3 laboratory abnormalities were rare.

Conclusions
G/P therapy for eight weeks in patients with chronic HCV GT 1–6 infection without cirrhosis achieved an overall SVR12 rate of 98% irrespective of baseline patient or viral characteristics; four additional weeks of treatment did not significantly increase the SVR12 rate, demonstrating that the optimal treatment duration in this population is eight weeks.

Lay summary
In this integrated analysis of nine clinical trials, patients with chronic HCV genotype 1–6 infection without cirrhosis were treated for either 8 or 12 weeks with the direct-acting antiviral regimen glecaprevir/pibrentasvir (G/P). The cure rate was 98% and 99% following 8 and 12 weeks of treatment, respectively; the difference in rates was not significant (p = 0.2), nor was there a significant difference in the cure rates across the two treatment durations on the basis of baseline patient or viral characteristics. These results, along with a favourable safety profile, indicate that G/P is a highly efficacious and well-tolerated pangenotypic eight-week therapy for most patients with chronic HCV infection.

Tuesday, June 12, 2018

Blogger Updates: Opioid & hepatitis C epidemic


Thanks for stopping by, we begin with an article about the opioid & hepatitis C epidemic, published today online over at Harvard Law;

Hepatitis C Virus Infection: Another Consequence of the Opioid Epidemic
HCV is matching the grim statistics of marching hand-in-hand with the opioid epidemic and we must make sure treatment is available to everyone.

In The News

Blog Updates
Welcome, check out the following patient bloggers who share tips and inspiring stories on the topic of viral hepatitis.

HepCBC 
Read a nice summary of notable headlines published in the latest issue of
The Weekly Bull.

Hep
Tray Tables Up, Hepatitis C on a Plane
Some unexpected turbulence from stigma and ignorance on a flight from an advocacy conference.

Understanding Hepatitis C Genotypes
Hepatitis C genotypes are like different races, or breeds, of the virus. Here is the long and the short of it...

Every so often, I’ll read an article or study about hepatitis C, and feel shaken to my core. “Long-Term Liver Disease, Treatment, and Mortality Outcomes Among 17,000 Persons Diagnosed with Chronic Hepatitis C Virus Infection” by Anne Moorman and colleagues is a core shaker. 

Liver disease such as viral hepatitis and other liver conditions can cause damage to the liver which can range from mild to severe. 

Longtime hepatitis C activist and advocate, Orlando Chavez died from a massive brain hemorrhage on June 3, 2018 in Oakland, CA. 

View all updates: Hep

HepatitisC.net
There are many lab tests done to help diagnosis liver disease. Understanding and tracking liver lab tests can help 

This is the sixth and final installment of a six-part series called The Fallout Guide for Hep C. Six emotional 

Kim’s article I Have Hep C, I Am Not Hep C. 

View all blog updates: HepatitisC.net 

Lucinda K. Porter 
Now I am turning 65. Hepatitis C is gone, and I’ve been thinking about goals. 

View all updates: Lucinda K. Porter 

ADRLF (Al D. Rodriguez Liver Foundation)
Alcohol’s Heart Benefits May Not Apply to People With Liver Disease
Numerous articles and videos circulated on social media and reputable websites, stating that light to moderate alcohol intake offers cardio-vascular health benefits. But does this apply to everyone? Studies show that it might not be the case for people with liver disease.

View all updates: ADRLF

Life Beyond Hepatitis C
Hep C Treatment Mile Markers
I discovered a very helpful way to get through Hep C Treatment with weekly achievable goals called Mile Markers. 

View all updates: Life Beyond Hepatitis C 

I Help C
When Adult Kids Disrespect You
When we’re dealing with chronic, ongoing health problems, it can mess up the way our family relates to one another. We don’t use it as an excuse. We use wise parenting skills.

View all updates: I Help C

Other Updates
Hepatitis B Foundation
World Hepatitis Day 2018: Why is Hepatitis B testing Important?
Help us raise awareness for World Hepatitis Day (July 28th, 2018) by telling the world why it is important to get tested for hepatitis B! Create an awareness message about hepatitis B by answering the prompt below.The Hepatitis B Foundation will compile video entries for a larger video that will be released on World Hepatitis Day, July 28, 2018.

View all updates: Hepatitis B Foundation 

Canadian Liver Foundation
Keeping your liver lively!
Much of the stress on your liver can be avoided with a proper regimen of healthy eating and exercise. Here are some more helpful tips that will help you get active, and keep your liver in tiptop shape!

When NASH becomes a family affair
After a battery of blood tests and a CT scan, doctors determined she had an enlarged liver due to a build-up of fat. Once she was referred to a liver specialist, further tests and a biopsy revealed that she had non-alcoholic steatohepatitis or NASH, the most severe form of NAFLD.

View all updates: Canadian Liver Foundation

Harvard Medical School
Six common depression types
Ongoing mood, cognitive changes may require professional help

Harvard Health
A new shingles vaccine is available and recommended for adults over age 50, regardless of whether they’ve had the older shingles vaccine in the past.

Vegetable of the month: Avocado
Avocados are one of the few fruits that contain healthy unsaturated fats. These fats help lower undesirable LDL cholesterol when eaten in place of saturated fat.

View all updates here: Harvard Health Blog 

Mayo Clinic
Your digestive tract, also called the gut, contains trillions of bacteria. Many of those bacteria play a number of useful roles in the body, including metabolizing nutrients from food. While much of the bacteria in the gut are valuable, some are not. There have been studies done about how an imbalance between good and bad gut bacteria could contribute to certain medical disorders.

View all updates: Mayo Clinic

University of Michigan
Video Conferencing Helps PCPs Improve Liver Disease Care, Survival Rates
Providing physicians with virtual access to specialists can be lifesaving to liver disease patients. A new study finds that it boosts survival rates by 54 percent. 

View all updates: Lab Blog

See you soon,
Tina

Photo Credit: https://www.pexels.com/

Saturday, June 2, 2018

Weekend Reading: When to Initiate HCV Therapy and Overview Of New Drugs


If you landed here this weekend looking for information about treating the hepatitis C virus (HCV), you're in luck!

Sit back, grab your favorite beverage and review; Making a Decision on When to Initiate HCV Therapy, updated a few days ago, published by Hepatitis C Online.

The site is free, and offers easy to comprehend learning activities with comprehensive information about diagnosing, monitoring and managing the virus.

In addition, check out the links below with an overview of FDA-approved drugs, including prescribing information, clinical studies, and slide decks, also provided by Hepatitis C Online. Finally, have a look see at the HCV Guidance to discover more about treating HCV according to your genotype.

Making a Decision on When to Initiate HCV Therapy
Last Updated: May 31st, 2018
Authors: John D. Scott, MD,
Sophie L. Woolston, MD

The American Association for the Study of Liver Disease and Infectious Diseases Society of America (AASLD-IDSA) notes that evidence clearly supports treatment of nearly all persons with chronic HCV infection. Decisions regarding initiating therapy will naturally be influenced by the patient's willingness and readiness to undertake treatment.

Summary Points
Availability of highly effective, convenient, safe, well-tolerated therapy has changed the landscape for the treatment of hepatitis C.

Nearly all patients with hepatitis C may benefit from therapy. Those patients with a severely limited lifespan (less than 12 months) are the exception.

The decision and timing for starting HCV therapy needs to be individualized.

In situations when treatment is deferred (for whatever reason), the patient should periodically undergo reevaluation for disease progression and reconsideration of treatment, with the frequency of reevaluation individualized based on the patient's current fibrosis stage, likely fibrosis progression rate, and other factors that may influence treatment readiness.
Download PDF

Hepatitis C Online Additional Reading - HCV Medications
Daclatasvir (Daklinza)
Elbasvir-Grazoprevir (Zepatier)
Glecaprevir-Pibrentasvir (Mavyret)
Ledipasvir-Sofosbuvir (Harvoni)
Ombitasvir-Paritaprevir-Ritonavir (Technivie)
Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak)
Peginterferon alfa-2a (Pegasys)
Peginterferon alfa-2b (PegIntron)
Ribavirin (Copegus, Rebetol, Ribasphere)
Simeprevir (Olysio)
Sofosbuvir (Sovaldi)
Sofosbuvir-Velpatasvir (Epclusa)

HCV Guidance 
The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America with the International Antiviral Society developed a living document with ever evolving guidelines to treat HCV. Here are a few links to get you started.

The following pages include guidance for management of treatment-naive patients.
Genotype 1
Genotype 2
Genotype 3
Genotype 4
Genotype 5 or 6

The following pages include guidance for management of treatment-experienced patients. 
Genotype 1
Genotype 2
Genotype 3
Genotype 4

Stay current with all guideline updates, "click here."

If you missed the June issue of newsletters, blog updates and recent publications, click here. Hope you have a lovely weekend!
Tina

Friday, April 13, 2018

First real-world data on Mavyret showing safety & effectiveness in HCV Genotype 1-6

Shared on Twitter today by @HenryEChang - First real-world data from the Deutsches Hepatitis C-Register (DHC-R) showing favorable safety & excellent effectiveness of G/P in HCV GT1-6 patients with 97% SVR12 & no virologic failures to date.

FIRST REAL - WORLD DATA ON SAFETY AND EFFECTIVENESS OF GLECAPREVIR/PIBRENTASVIR FOR THE TREATMENT OF PATIENTS WITH CHRONIC HEPATITIS C VIRUS INFECTION: DATA FROM THE GERMAN HEPATITIS C - REGISTRY


Download it here.... http://jmp.sh/VthHp48



Mavyret (glecaprevir/pibrentasvir)
Liver Congress™ 2018 First real-world studies report glecaprevir/pibrentasvir to be effective and well tolerated in chronic HCV infection
April 12, 2018
The results of the first real-world studies assessing the effectiveness and safety of glecaprevir/pibrentasvir (G/P) in patients with chronic hepatitis C virus (HCV) infection have confirmed high rates of viral suppression and a favourable safety profile in patients receiving 8-16 weeks of treatment.

Real-world experience confirms Mavyret efficacy in HCV
April 12, 2018
PARIS — Two real-world studies presented at the International Liver Congress 2018 confirmed the efficacy and safety of Mavyret in Italy and…

Saturday, December 2, 2017

Mavyret: A Pan-Genotypic Combination Therapy for the Treatment of Hepatitis C Infection

Published as part of the Biochemistry series “Biochemistry to Bedside”
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States
DOI: 10.1021/acs.biochem.7b01160
Publication Date (Web): December 1, 2017
Copyright © 2017 American Chemical Society

Viewpoint
Mavyret: A Pan-Genotypic Combination Therapy for the Treatment of Hepatitis C Infection
Ashley N. Matthew, Nese Kurt Yilmaz, and Celia A. Schiffer

Hepatitis C virus (HCV), a virus that infects more than 180 million people worldwide, is the causative agent of chronic liver disease, which often progresses to fibrosis, liver cirrhosis, and hepatocellular carcinoma (HCC). According to the World Health Organization, almost half a million patients infected with HCV die each year from cirrhosis and HCC alone. In the last several years, treatment of HCV infections has been revolutionized by the development of small molecular inhibitors that target essential proteins encoded by the viral genome. These inhibitors, known as direct-acting antivirals (DAAs), have improved treatment option and outcomes and eliminated the need for interferon injections. However, the emergence of resistance-associated variants (RAVs) and high genetic variation among the six distinct genotypes of the virus have been presenting challenges, even leading to treatment failure.

Newer all-oral DAA combination regimens for HCV infection consist of inhibitors that target the NS3/4A, NS5A, and NS5B viral proteins. Of note, NS3/4A protease inhibitors have become a mainstay of treatment as most new therapies contain an inhibitor from this class. While highly effective against other genotypes, treatment of genotype 3 infections has been the most challenging, especially in patients who failed previous therapy or have cirrhosis. Recently, AbbVie received Food and Drug Administration (FDA) approval for one of the first pan-genotypic combination therapies, Mavyret, consisting of glecaprevir and pibrentasvir, an NS3/4A protease and an NS5A inhibitor, respectively (Figure 1). Given the excellent pan-genotypic response and safety profile in patients, Mavyret was approved for the treatment of genotypes 1–6 in patients without cirrhosis, or with compensated cirrhosis. In patients with non-cirrhotic chronic HCV who were treatment-naïve or had previously been treated with pegylated interferon or ribavirin, the sustained virological response (SVR) rate was 83–100% across all genotypes.(1) In treatment-naïve patients with compensated liver disease, 99% of patients achieved SVR with a 12-week course.(2) Mavyret was approved as an 8-week course for treatment-naïve patients without cirrhosis, shortening the previous standard of care by an additional 4 weeks.

One component of the Mavyret combination, pibrentasvir (ABT-530), has excellent potency across all HCV genotypes and retains potency against common RAVs. Pibrentasvir had EC50 values across genotypes ranging from 1.4 to 5 pM against the HCV replicon in antiviral assays.(3) Under the selective pressure of inhibitors, RAVs emerge at positions 28, 30, 31, and 93 in the NS5A protein. In fact, all current NS5A inhibitors are susceptible to mutations at Tyr93. In vitro studies indicate pibrentasvir also selects these mutations, including Y93H, that confer resistance to other NS5A inhibitors.(3) However, pibrentasvir maintained good potency against many single-site NS5A mutations, suggesting double or triple mutants need to emerge to confer high levels of resistance against this inhibitor.

The other component of Mavyret, glecaprevir (ABT-493), is a P2–P4 macrocyclic NS3/4A protease inhibitor with subnanomolar to low nanomolar activity against all genotypes, including genotype 3.(4) NS3/4A protease inhibitors are often susceptible to single-site mutations at residues Arg155, Ala156, and Asp168. Most if not all protease inhibitors are susceptible to mutations at Asp168, which are often present in patients who fail therapy with a protease inhibitor. Notably, this active site residue is not conserved in genotype 3 and is Gln168 instead, contributing to the natural resistance of genotype 3 to most treatments. While potent against 168 variations, including genotype 3, glecaprevir is highly susceptible to A156T and A156V mutations. We have shown that inhibitors containing P2–P4 macrocycles, as in glecaprevir, are susceptible to changes at Ala156, as substitutions with a larger side chain result in steric clash with the inhibitor’s macrocycle.(5) Luckily, mutations at Ala156 do not occur alone because of reduced replicative capacity; however, additional mutations could restore the enzymatic fitness, which can lead to clinically viable multi-mutant resistant variants.

Thus, both components of Mavyret have good resistance profiles against wild type genotypes and single-mutant variants of HCV. What needs to be considered is the emergence of double, triple, or other multi-mutant variants that may have high levels of resistance to one or both components of this combination. Such multi-mutant variants potentially pose a threat to the longevity and success of HCV treatment. There are already double- and triple-mutant variants that have been isolated from patients who failed therapy with previously FDA-approved combination therapies. Considering the similarity in the inhibitor scaffolds and modes of action, there is a danger that these variants may be cross-drug resistant and not respond to any current treatment option, including Mavyret. As new drugs and combinations are developed, it will be important to understand the mechanisms of resistance for these multi-mutant variants and incorporate those insights into drug design. Rather than concentrating all effort into inhibitors from the same class with highly similar scaffolds, diversifying the arsenal of DAAs and considering triple-combination therapy may be required to avoid cases of incurable HCV infection.

The approval of Mavyret dual-combination therapy marks another milestone in the treatment of HCV infections. There had been a major effort to develop an all-oral combination therapy with activity against all genotypes. With the approval of Mavyret, this goal has been met. The newer-generation inhibitors and various combinations provide treatment options for patients and improve SVR rates across all genotypes. For many cases, Mavyret has decreased the standard of care from 24 to 8 weeks. More importantly, treatment options for patients with compensated liver disease are now available. One major remaining concern is the possible emergence of drug resistance. The newer inhibitors have better activity against single-site RAVs, but highly resistant multi-mutant strains may become clinically relevant. Preventing the emergence and spread of cross-resistant variants and developing inhibitors with improved potency against such variants may be the next challenge.

Full Text

Saturday, November 25, 2017

Drug resistance-associated substitutions identified in HCV genes

Gastroenterology 2017
View Abstract
DOI: http://dx.doi.org/10.1053/j.gastro.2017.11.007

Commentary
Drug resistance-associated substitutions identified in HCV genes
Last Updated: 2017-11-24
By Marilynn Larkin
NEW YORK (Reuters Health) - In patients who fail direct-acting antiviral therapy for hepatitis C virus (HCV) infection, resistance-associated substitutions (RASs) vary by HCV genotype and subtype and with different classes of drugs - a finding that might be used to select salvage therapies, researchers suggest.

"Little is known about (genetic) substitutions that mediate resistance of HCV to direct-acting antivirals, due to the small number of patients with treatment failure in approval studies," note Dr. Christoph Sarrazin of the University of Frankfurt, in Germany, and colleagues.
To investigate, the team analyzed samples from patients who had HCV infection with genotypes 1 to 6 for RASs in HCV genes (NS3, NS5A, NS5B) that are targeted by direct-acting antivirals.
Continue to article - http://www.chronicliverdisease.org/reuters/article.cfm?article=20171124Other832489063

Tuesday, October 17, 2017

The changing HCV treatment cascade

Pharmacology Consult
The changing HCV treatment cascade
Infectious Disease News, October 2017
Jocelyn Mason, PharmD; Kimberly D. Boeser, PharmD, MPH, BCPS, AQ-ID
The rapid development of DAA combinations provides simplified regimens, shorter durations, improved efficacy and greater tolerability, unlike the previous interferon and ribavirin cornerstone regimens. Although the IDSA/AASLD guidelines provide the map to managing HCV, they do not identify the ideal interferon-free regimen to begin with, nor have they given a clear path to treating genotype 3 and those with decompensated cirrhosis. This ever-changing field will require collaboration among health care providers, including those specializing in infectious diseases, hepatology and gastroenterology, as well as pharmacists, to optimize treatment strategies. As the landscape of HCV continues to update with new literature and new medications, this subspecialty continues to be dynamic.
Continue to article - https://www.healio.com/infectious-disease/hepatitis-c/news/print/infectious-disease-news/%7B87b74536-f358-43d3-a804-f37a98402b0b%7D/the-changing-hcv-treatment-cascade

Wednesday, September 27, 2017

Japan - AbbVie Announces Approval of MAVIRET™ (glecaprevir/pibrentasvir) of Chronic Hepatitis C in All Major Genotypes (GT1-6)

AbbVie Announces Approval of MAVIRET™ (glecaprevir/pibrentasvir) for the Treatment of Chronic Hepatitis C in All Major Genotypes (GT1-6) in Japan

- MAVIRET is the first and only 8-week treatment for genotype 1 and 2 hepatitis C virus (HCV) infected patients without cirrhosis and who are new to DAA treatment* in Japan
- Approval is supported by a 99 percent virologic cure** rate in these patients, who comprise the majority of people living with HCV (1,2)
- AbbVie's pan-genotypic, ribavirin-free treatment was recently approved for use in the European Union and United States
- Japan has one of the highest rates of HCV infection in the industrialized world (2,3)

NORTH CHICAGO, Ill., Sept. 27, 2017 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global research and development-based biopharmaceutical company, today announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) approved MAVIRET™ (glecaprevir/pibrentasvir), a once-daily, ribavirin-free treatment for adults with chronic hepatitis C virus (HCV) infection across all major genotypes (GT1-6). MAVIRET is the first and only 8-week treatment option in Japan for GT1 and GT2 HCV infected patients without cirrhosis and who are new to direct-acting antiviral (DAA) treatment,* including those with chronic kidney disease (CKD). These patients represent the majority of people living with HCV in Japan.2

In Japan, MAVIRET is also a 12-week option for patients infected with GT3-6, patients with specific treatment challenges including patients with compensated cirrhosis, and those with limited treatment options such as those not cured with previous DAA treatment.1

"New pan-genotypic, ribavirin-free treatments like MAVIRET that have a short treatment duration have the potential to become a first-line HCV treatment option and will also be fundamental to addressing challenges that remain in the care of this serious and complex disease in Japan," said Hiromitsu Kumada, M.D., Director General, Department of Hepatology, Toranomon Hospital Kajigaya, Kanagawa, Japan. "High cure rates were shown in dedicated clinical trials with MAVIRET in Japanese patients, as well as a favorable tolerability profile, demonstrating the potential of MAVIRET to meet evolving unmet needs for both patients and physicians."

Japan has one of the highest rates of HCV infection in the industrialized world, with approximately 2 million people living with the disease, 97 percent of whom are infected with GT1 and GT2 chronic HCV.2,3 Japan also has the highest prevalence of liver cancer amongst the industrialized countries with chronic hepatitis C and its complications being the leading causes.4

"The human, social and economic burden of HCV to individuals in Japan can be significant as the disease progresses to the later stages," said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. "AbbVie is committed to working with health authorities to get MAVIRET to physicians and patients as quickly as possible, so that the opportunity for virologic cure in as short as 8 weeks may be a reality for the majority of people living with HCV."

Authorization is supported by data from the Phase 3 CERTAIN studies in Japanese patients and supplemented with registrational studies from AbbVie's global clinical development program for MAVIRET. With just 8 weeks of treatment, a 99 percent (n=226/229) SVR12 rate was achieved across GT1 and GT2 chronic HCV infected Japanese patients without cirrhosis and who were new to DAA treatment.*1 This high SVR12 rate was achieved in patients with varied patient and viral characteristics and including those with CKD.1 In patients not cured with previous DAA treatment, a 94 percent (n=31/33) SVR12 rate was achieved with 12 weeks of treatment. The most commonly reported adverse reactions were pruritus, headache, malaise and blood bilirubin increase (none of which had an incidence greater than 5 percent).1

MAVIRET combines two new, potent§ direct-acting antivirals that target and inhibit proteins essential for the replication of the hepatitis C virus. The presence of more difficult-to-treat genotypes or baseline mutations that are commonly associated with resistance have been shown to have minimal impact on efficacy of MAVIRET.

Approval of MAVIRET follows priority review, designated by the Japanese MHLW to certain medicines based on the clinical usefulness of the treatment and severity of the disease. AbbVie's pan-genotypic treatment was also recently granted marketing authorization by the European Commission and approved by the U.S. Food and Drug Administration as an 8-week, pan-genotypic treatment for patients without cirrhosis and who are new to treatment.

*Patients without previous treatment that included a DAA (direct-acting antiviral) NS3/4A protease inhibitor, NS5A inhibitor and/or NS5B polymerase inhibitor.
**Patients who achieve a sustained virologic response at 12 weeks post treatment (SVR12) are considered cured of hepatitis C.

Based on EC50 values of glecaprevir and pibrentasvir against full-length or chimeric replicons encoding NS3 or NS5A from laboratory strains and chimeric replicons from clinical isolates.

Tuesday, September 26, 2017

Hepatitis C cross-genotype immunity and implications for vaccine development

Hepatitis C cross-genotype immunity and implications for vaccine development
Nazrul Islam, Mel Krajden, Jean Shoveller, Paul Gustafson, Mark Gilbert, Jason Wong, Mark W. Tyndall, Naveed Zafar Janjua & The BC-HTC Team
Received:
Accepted:
Published online:

  • Scientific Reports 7, Article number: 12326 (2017)
  • doi:10.1038/s41598-017-10190-8

  • Abstract
    While about a quarter of individuals clear their primary hepatitis C (HCV) infections spontaneously, clearance (spontaneous or treatment-induced) does not confer sterilizing immunity against a future infection. Since successful treatment does not prevent future infections either, an effective vaccine is highly desirable in preventing HCV (re)infection. However, development of an effective vaccine has been complicated by the diversity of HCV genotypes, and complexities in HCV immunological responses. Smaller studies on humans and chimpanzees reported seemingly opposing results regarding cross-neutralizing antibodies. We report a lack of cross-genotype immunity in the largest cohort of people to date. In the adjusted Cox proportional hazards model, reinfection with a heterologous HCV genotype (adjusted Hazard Ratio [aHR]: 0.45, 95% CI: 0.25–0.84) was associated with a 55% lower likelihood of re-clearance. Among those who cleared their first infection spontaneously, the likelihood of re-clearance was 49% lower (aHR: 0.51, 95% CI: 0.27–0.94) when reinfected with a heterologous HCV genotype. These findings indicate that immunity against a particular HCV genotype does not offer expanded immunity to protect against subsequent infections with a different HCV genotype. A prophylactic HCV vaccine boosted with multiple HCV genotype may offer a broader and more effective protection.

    Continue to article.....

    Monday, September 25, 2017

    Gilead's Sovaldi® (Sofosbuvir) Approved In China for Treatment of Chronic Hepatitis C

    China Food and Drug Administration Approves Gilead's Sovaldi® (Sofosbuvir) for Treatment of Chronic Hepatitis C Virus Infection

    - Sovaldi-based Regimens Demonstrated High Rates of Sustained Virologic Response or Cure for Chinese Hepatitis C Infected Patients -

    FOSTER CITY, Calif.--(BUSINESS WIRE)--Sep. 25, 2017-- Gilead Sciences, Inc. (NASDAQ: GILD) announced today that the China Food and Drug Administration (CFDA) has approved Sovaldi® (sofosbuvir 400mg), a once-daily oral nucleotide analog polymerase inhibitor for the treatment of chronic hepatitis C virus (HCV) infection. Sovaldi was approved for the treatment of adults and adolescents (aged 12 to 18 years) infected with HCV genotype 1, 2, 3, 4, 5 or 6 as a component of a combination antiviral treatment regimen. Sovaldi is the first Gilead HCV medicine approved in China.
      
    The approval of Sovaldi is supported by a Phase 3 study conducted in China, presented earlier this year at the Asian Pacific Association for the Study of the Liver (APASL) meeting. SVR12 (HCV RNA undetectable 12 weeks after completing therapy) rates for Chinese HCV patients with genotype 1, 2, 3 or 6 ranged from 92-100 percent. The study evaluated Sovaldi in combination with ribavirin (RBV) or pegylated interferon+ribavirin (PegIFN+RBV) across a range of difficult-to-cure patient populations, including treatment-experienced patients and those with compensated cirrhosis. In this study, the safety profiles of the regimens were consistent with the known side effects of pegylated interferon and/or ribavirin. The most common adverse events were hematological abnormalities and pyrexia.
      
    Professor Lai Wei, the principal investigator of Sovaldi’s Phase 3 study and former Chairman of the Chinese Society of Hepatology of the Chinese Medical Association said, “The approval of sofosbuvir in China provides more treatment options for Chinese HCV patients. The clinical trials in China and around the world provide evidence that the treatment is effective for multiple genotypes, which offers HCV patients in China a better chance at curing their disease.”
      
    HCV is the fourth-most commonly reported infectious disease in China, with approximately 10 million people infected. HCV genotypes 1, 2, 3 and 6 account for more than 96 percent of all cases. Less than one percent of HCV patients are currently treated, using interferon-based regimens that have lower efficacy, longer treatment duration and less favorable safety profiles than more recent regimens that contain direct-acting antiviral medicines.
      
    “With the approval of Sovaldi, there is now the potential opportunity to transform treatment for HCV patients in China,” said John F. Milligan, PhD, Gilead’s President and Chief Executive Officer. “Medicines are one part of the solution but, as we have seen in other countries around the world, there are many other challenges that impact diagnosis, linkage to care and treatment. Gilead is committed to working with the government and other stakeholders with the goal to help reduce the significant burden of HCV disease in China.”
      
    Sovaldi received marketing approval from the U.S. Food and Drug Administration (FDA) in 2013 and the European Commission in 2014. It is also approved for use in 79 countries including Australia, India, Indonesia, the Philippines, New Zealand, Canada, Egypt, Switzerland and Turkey.

    Saturday, August 26, 2017

    The new paradigm in the treatment of chronic hepatitis C disease: Faster, Higher and Stronger

    Citius Altius Fortius: The new paradigm in the treatment of chronic hepatitis C disease

    Aug 26, 2017

    Download Full Text Article
    Provided By Henry E. Chang‏ via Twitter

    Abraham GM, et al. – This study focuses on the treatment of chronic hepatitis C disease. Findings reveal that most of the direct–acting antiviral agents (DAAs) for chronic hepatitis C infection had a high barrier to resistance and are extremely well–tolerated by patients. DAAs, in addition, demonstrate 90% or higher efficacy rates.
    • The treatment paradigm for chronic hepatitis C infection has dramatically changed with the advent of the direct–acting antiviral agents (DAAs), especially the duration, tolerability and response to therapy.
    • The DAAs are classified in to several classes and are variously indicated in the treatment of one or more genotypes of infection.
    • All these agents are orally administered, and they, in majority, are eliminated renally (with exceptions), and don'’t require adjustment in mild to moderate renal insufficiency.
    Abstract
    With the advent of the direct-acting antiviral agents (DAAs) for chronic hepatitis C infection, the treatment paradigm has dramatically changed, especially the duration, tolerability and response to therapy. The DAAs fall into several classes and are variously indicated in the treatment of one or more genotypes of infection. All these agents are orally administered, and they are largely renally eliminated (with exceptions), don’t require adjustment in mild to moderate renal insufficiency. Most of these agents demonstrate a high barrier to resistance and are extremely well-tolerated by patients. Overall efficacy rates are 90% or higher.
    Download Article

    Of Interest
    Systematic review: cost-effectiveness of DAAs for treatment of HCV genotypes 2-6

    New At Hepatitis C Online:
    Vosevi and Mavyret
    Information on Gilead's newly FDA approved Vosevi and AbbVie's Mavyret  is now available.

    Full Text Articles
    I highly suggest you follow Henry E. Chang on Twitter if you are interested in reading full text articles about the treatment and management of hepatitis C.

    Thursday, August 17, 2017

    AbbVie's MAVIRET Approved by Health Canada

    AbbVie's MAVIRET™ Approved by Health Canada for the Treatment of Chronic Hepatitis C in All Major Genotypes

    MAVIRET is the first and only 8-week, pan-genotypic treatment for hepatitis C patients without cirrhosis and who are new to treatment*1
    The approval is supported by a 97 percent (n=639/657) cure** rate across GT1-6 patients without cirrhosis and who are new to treatment2
    MAVIRET is the only pan-genotypic treatment approved for use in patients across all stages of chronic kidney disease


    MONTREAL, Aug. 17, 2017 /CNW/ - AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced that Health Canada has granted approval for MAVIRET™ (glecaprevir/pibrentasvir tablets), a once-daily, ribavirin-free treatment for adults with chronic hepatitis C virus (HCV) infection across all major genotypes (GT1-6). MAVIRET is the only 8-week, pan-genotypic treatment for patients without cirrhosis and who are new to treatment,* who make up a large portion of HCV patients in Canada.

    "Despite recent advances in HCV treatment, physicians still face challenges treating patients with less common genotypes and those with other complicating health conditions," said Dr. Morris Sherman, MD, FRCPC, Chairperson, Canadian Liver Foundation. "In order to eliminate hepatitis C in Canada, we need to identify all those living with the virus and have effective treatment options for everyone. This new therapy provides another tool for physicians to expand treatment to a greater number of patients while at the same time shortening the duration which may lead to cost savings for the health care system."

    MAVIRET is also approved for use in patients with specific treatment challenges, including those with compensated cirrhosis across all major genotypes, and those who previously had limited treatment options, such as patients with severe chronic kidney disease (CKD), those GT1 patients not previously cured with certain direct-acting antiviral (DAA) treatment, and those with GT3 chronic HCV infection.2 MAVIRET is the only pan-genotypic treatment approved for use in patients across all stages of CKD.2

    "With the approval of MAVIRET, we are proud to bring the hope of a new cure to people living with hepatitis C in Canada, reflecting AbbVie's dedication to addressing critical unmet needs for patients," said Stéphane Lassignardie, General Manager, AbbVie Canada. "MAVIRET is designed to deliver a virologic cure for most HCV patients including those with specific treatment challenges. AbbVie will continue to work with local health authorities and stakeholders across Canada to get our treatment to as many patients as possible."

    The efficacy and safety of MAVIRET was evaluated in nine Phase 2-3 clinical trials, in over 2,300 patients with genotype 1, 2, 3, 4, 5 or 6 HCV infection and with compensated liver disease (with or without cirrhosis).

    Approximately 300,000 Canadians are infected with hepatitis C.3 In 2012 alone, more than 10,000 new cases of hepatitis C were reported, but 40 percent of patients are estimated to be living unaware of their disease.4 GT1 is the most common genotype in Canada and GT3 is the most difficult to treat.3,5 Over time chronic hepatitis C can lead to chronic liver diseases, with a risk of developing cirrhosis of up to 30 percent within 20 years6 of infection. Additionally, HCV is common among people with severe CKD, and some of these patients previously did not have a DAA-based treatment option.7

    With 8 weeks of treatment, 97 percent (n= 639/657) of GT1-6 patients without cirrhosis and who were new to treatment achieved a virologic cure.1 These high cure rates were achieved in patients with varied patient and viral characteristics and including those with CKD.2 Additionally, 97.5 percent (n=274/281) of patients with compensated cirrhosis achieved a virologic cure with the recommended duration of treatment, including patients with CKD.2 In registrational studies for MAVIRET, less than 0.1 percent of patients permanently discontinued treatment due to adverse reactions.2 The most commonly reported adverse reactions (incidence greater than or equal to 10 percent) were headache and fatigue.2

    "In an extensive clinical trial program, patients achieved high cure rates with MAVIRET regardless of genotype, fibrosis score, viral load, and even in patients with resistant virus strains and those with chronic kidney disease," said Dr. Magdy Elkhashab, Gastroenterologist/Hepatologist, Director of the Toronto Liver Centre. "In clinical practice, MAVIRET has the potential to simplify treatment decisions for physicians, offering, in one therapy, a cure for the majority of HCV patients and cutting out pre-testing before treatment initiation."

    MAVIRET combines two new, potent direct-acting antivirals that target and inhibit proteins essential for the replication of the hepatitis C virus.2 The presence of most genotypes or baseline mutations that are commonly associated with resistance have been shown to have no relevant impact on efficacy.2

    Canadians prescribed MAVIRET will have the opportunity to be enrolled in AbbVie Care, AbbVie's signature patient support program designed to provide a wide range of services including reimbursement assistance, education and ongoing disease management support. AbbVie Care will support people living with HCV throughout their treatment journey to achieve high cure rates in the real world.

    Approval of MAVIRET followed Health Canada's Priority Review process, which is granted to new medicines intended for patients with a life-threatening disease where there is no existing treatment with the same profile or where the new product represents a significant improvement in the benefit/risk profile over existing products.8 AbbVie's investigational, pan-genotypic regimen was also recently approved by the European Commission and the U.S. Food and Drug Administration.

    About MAVIRET™
    MAVIRET™ is approved in Canada for the treatment of chronic hepatitis C virus (HCV) infection in adults across all major genotypes (GT1-6).2 MAVIRET is a new, pan-genotypic, once-daily, ribavirin-free treatment that combines glecaprevir (100 mg), an NS3/4A protease inhibitor, and pibrentasvir (40 mg), an NS5A inhibitor, dosed once-daily as three oral tablets.2

    MAVIRET is an 8-week, pan-genotypic virologic cure** for use in patients without cirrhosis and who are new to treatment,* such patients comprising the majority of people living with HCV.1 MAVIRET is also approved as a treatment for patients with specific treatment challenges, including those with compensated cirrhosis across all major genotypes, and those who previously had limited treatment options, such as patients with severe chronic kidney disease (CKD) and those with genotype 3 infection.2 It is the only pan-genotypic treatment approved for use in patients across all stages of CKD.2

    Glecaprevir (GLE) was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors.

    *Patients without cirrhosis and new to treatment with DAAs [either treatment-naive or not cured with previous IFN-based treatments ([peg]IFN +/- RBV or SOF/RBV +/- pegIFN)].
    **Patients who achieve a sustained virologic response at 12 weeks post treatment (SVR12) are considered cured of hepatitis C.

    About AbbVie
    AbbVie is a global, research-driven biopharmaceutical company committed to developing innovative advanced therapies for some of the world's most complex and critical conditions. The company's mission is to use its expertise, dedicated people and unique approach to innovation to markedly improve treatments across four primary therapeutic areas: immunology, oncology, virology and neuroscience. In more than 75 countries, AbbVie employees are working every day to advance health solutions for people around the world. For more information about AbbVie, please visit us at www.abbvie.ca and www.abbvie.com. Follow @abbvieCanada and @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

    1 Decisions Resources Group. Hepatitis C virus: disease landscape & forecast 2016. January 2017.
    2 MAVIRET (glecaprevir/pibrentasvir tablets) Product Monograph. Date of Preparation: August 16, 2017.
    3 Messina, JP et al. "The global distribution of HCV genotypes." Hepatology, 2015; 61: 77–87. Supporting information hep27259-sup-0001-suppinfo.pdf. Accessed August, 2017.
    4 Hepatitis C: Get the Facts. Government of Canada. https://www.canada.ca/en/public-health/services/publications/diseases-conditions/poster-hepatitis-c-get-facts.html. Accessed August, 2017.
    5 Wyles, D et al. SURVEYOR-II, Part 3: Efficacy and Safety of ABT-493/ABT-530 in Patients with Hepatitis C Virus Genotype 3 Infection with Prior Treatment Experience and/or Cirrhosis. Presented at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, US on November 11-15, 2016.
    6 Hepatitis C Fact Sheet. World Health Organization. World Health Organization, July 2017. Web. http://www.who.int/mediacentre/factsheets/fs164/en/. Accessed August, 2017.
    7 Fabrizi F, Poordad FF, Martin P. Hepatitis C infection in the patient with end stage renal disease. Hepatology. 2002;36(1):3-10.
    8 Priority Review of Drug Submissions. Government of Canada. https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/fact-sheets/priority-review-drug-submissions-therapeutic-products.html. Accessed August, 2017.

    SOURCE AbbVie Canada
    For further information: Media: Muriel Haraoui, AbbVie Canada, (514) 717-3764, muriel.haraoui@abbvie.com

    Friday, July 21, 2017

    BVHG/BASL/BSG/BHIVA/BIA/CVN Guidelines for management of chronic HCV infection

    HCV consensus treatment guidelines

    BVHG/BASL/BSG/BHIVA/BIA/CVN Guidelines for management of chronic HCV infection

    Download PDF

    Preface
    These guidelines were generated following a consensus meeting held in Birmingham on the 30th of June 2017 of representatives from the above organisations as well as representatives from the operational delivery networks in England. They are intended to reflect best practice rather than what is currently commissioned for HCV treatment.
     
    Headline Recommendations


    1. We recommend that NHSE considers commissioning pan-genotypic regimens for use in the community for patients who are treatment naïve and do not have cirrhosis to avoid the need for genotyping and facilitate rapid access to care.  

    2. We recommend that ribavirin be avoided whenever possible.

    3. We recommend that 8 week regimens without ribavirin are first choice for treatment naïve non-cirrhotic patients treated in community or prison settings regardless of genotype.

    4. We reiterate that transplantation is not contra-indicated in patients with HCV even in the presence of ‘difficult’ drug resistant mutations.

    5 Drug-drug interactions should continue to be assessed and therapy should take account of potential interactions.

    Genotype Specific Recommendations

    Non-cirrhotic

    G1a
    Sofosbuvir/ledipasvir 8 weeks (treatment naïve) or 12 weeks (treatment experienced) Grazoprevir/elbasvir 12 weeks OR 16 weeks + ribavirin  for patients with viral load >800,000 and resistance associated substitutions(16 weeks + ribavirin is NOT a preferred regimen) Paritaprevir/ritonavir/ombitasvir+dasabuvir+ribavirin 12 weeks – should be discarded when Glecaprevir/pibrentasvir is available. Sofosbuvir/velpatasvir 12 weeks Sofosbuvir/velpatasvir/voxilaprevir - 8 weeks Glecaprevir/pibrentasvir - 8 weeks 

    G1b
    Sofosbuvir/ledipasvir 8 weeks (treatment naïve) or 12 weeks (treatment experienced) Grazoprevir/elbasvir 12 weeks Paritaprevir/ritonavir/ombitasvir+dasabuvir 12 weeks– should be discarded when Glecaprevir/pibrentasvir is available. Sofosbuvir/velpatasvir 12 weeks Sofosbuvir/velpatasvir/voxilaprevir 8 weeks Glecaprevir/pibrentasvir 8 weeks

    Compensated cirrhosis

    G1a
    Sofosbuvir/ledipasvir 12 weeks Grazoprevir/elbasvir 12 weeks OR 16 weeks + ribavirin for patients with viral load >800,000 and resistance associated substitutions (16 weeks + ribavirin is NOT a preferred regimen) Paritaprevir/ritonavir/ombitasvir+dasabuvir+ribavirin 12-24 weeks - should be discarded when Glecaprevir/pibrentasvir is available. Sofosbuvir/velpatasvir 12 weeks Sofosbuvir/velpatasvir/voxilaprevir 12 weeks  Glecaprevir/pibrentasvir 12 weeks

    G1b
    Sofosbuvir/ledipasvir 12 weeks Grazoprevir/elbasvir 12 weeks  Paritaprevir/ritonavir/ombitasvir+dasabuvir 12 weeks - should be discarded when Glecaprevir/pibrentasvir is available. Sofosbuvir/velpatasvir 12 weeks
    Sofosbuvir/velpatasvir/voxilaprevir 12 weeks Glecaprevir/pibrentasvir 12 weeks

    Decompensated cirrhosis

    G1a &1b
    Sofosbuvir/ledipasvir +/- ribavirin 12 weeks  Sofosbuvir/velpatasvir + ribavirin 12 weeks

    Re-treatment for DAA failures Requires pre-treatment virological sequencing to identify resistance associated variants whose presence/absence should be used to guide treatment decisions.

    Sofosbuvir/velpatasvir/voxilaprevir 12 weeks Glecaprevir/pibrentasvir  12 weeks (no prior NS5A) or 16 weeks (prior NS5A)

    Decompensated cirrhosis – retreatment requires Sof/vel +/- riba 24 weeks 

    G2
    Non cirrhotic
    Strongly recommend that IFN is removed and ribavirin free regimens are preferred. Sof/Vel 12 weeks Sof/Vel/Vox 8 weeks Glecaprevir/pibrentasvir 8 weeks

    G2
    Cirrhosis
    Sof/Vel 12 weeks Sof/vel/vox 12 weeks Glecaprevir/pibrentasvir 12 weeks
    Decompensated cirrhosis Sof/vel +/- riba 12 weeks 

    Re-treatment of DAA failures Requires pre-treatment virological sequencing to identify resistance associated variants whose presence/absence should be used to guide treatment decisions.

    Sofosbuvir/velpatasvir/voxilaprevir 12 weeks Glecaprevir/pibrentasvir  16 weeks

    G3
    Non cirrhotic
    Sof/Vel 12 weeks Sof/Vel/Vox 8 weeks Glecaprevir/pibrentasvir 8 weeks

    Cirrhotic
    Sof/Vel 12 weeks Sof/Vel/Vox 12 weeks Glecaprevir/pibrentasvir 16 weeks

    Decompensated cirrhosis 12 weeks sofosbuvir/velpatasvir +ribavirin. Consideration should be given to the use of sof/vel for 24 weeks in patients deemed unlikely to respond or intolerant of ribavirin.  

    Re-treatment for DAA failures Requires pre-treatment virological sequencing to identify resistance associated variants whose presence/absence should be used to guide treatment decisions.

    Sofosbuvir/velpatasvir/voxilaprevir 12 weeks
    Decompensated cirrhosis – retreatment requires Sof/vel +/- riba 24 weeks 

    G4
    Non Cirrhotic 
    Given the paucity of data and the availability of better-validated regimens we recommend that the use of sofosbuvir/ledipasvir for patients with Genotype 4 HCV should be discontinued. 

    Grazoprevir/elbasvir 12   Paritaprevir/ritonavir/ombitasvir 12 weeks - should be discarded when Glecaprevir/pibrentasvir is available. Sofosbuvir/velpatasvir/voxilaprevir 8 weeks  Sofosbuvir/velpatasvir 12 weeks Glecaprevir/pibrentasvir 8 weeks Cirrhosis Grazoprevir/elbasvir 12 OR 16 weeks  Sofosbuvir/velpatasvir 12 weeks Paritaprevir/ritonavir/ombitasvir 12 weeks - should be discarded when Glecaprevir/pibrentasvir is available. Sofosbuvir/velpatasvir/voxilaprevir 12 weeks Glecaprevir/pibrentasvir 12 weeks

    Decompensated cirrhosis
    12 weeks sofosbuvir/velpatasvir +ribavirin.
    Re-treatment for DAA failures Requires pre-treatment virological sequencing to identify resistance associated variants whose presence/absence should be used to guide treatment decisions.

    Sofosbuvir/velpatasvir/voxilaprevir 12 weeks Glecaprevir/pibrentasvir 16 weeks

     G5/6
    The small number of patients G5/6 infection in trials reported to date was noted. 
    Non cirrhotic
    Sof/Vel 12 weeks Glecaprevir/pibrentasvir 8-12weeks Sof/Vel/Vox 8 weeks

    Cirrhotic
    Sofosbuvir/velpatasvir 12 weeks Glecaprevir/pibrentasvir 12 weeks Sof/vel/vox 8 weeks

    Decompensated cirrhosis
    12 weeks sofosbuvir/velpatasvir +ribavirin.

    Re-treatment for DAA failures Requires pre-treatment virological sequencing to identify resistance associated variants whose presence/absence should be used to guide treatment decisions.

    Sofosbuvir/velpatasvir/voxilaprevir 12 weeks Glecaprevir/pibrentasvir 16 weeks (note that in patients with both NS5A and NS3 resistance associated variants this regimen is likely to be inadequate)

     Special Patient Categories

    Patients with renal impairment We recommend treatment as above but recommend that sofosbuvir be avoided in patients with GFR <45 ml/min.

    HIV-hepatitis C coinfection

    We recommend that patients with HIV-hepatitis C coinfection are treated for chronic hepatitis C with the same DAA-based treatment regimens as patients
    with hepatitis C mono-infection, although consideration of drug-drug interactions between DAAs and antiretrovirals should be taken into account.   We recommend that where HIV therapy cannot be switched to avoid drug-drug interactions, an appropriate alternate DAA-based regimen is identified.

    Acute hepatitis C infection

    We note emerging data shows public health benefits with early DAA therapy for patients with acute HCV who are at high risk of transmission. We recognize that pegylated interferon and ribavirin (the only current treatment option) is unlikely to be acceptable to patients and we therefore recommend that DAA-based treatment is made available for the treatment of acute and early hepatitis C infection, replacing pegylated-interferon +/- ribavirin 24 to 48 weeks

     Re-infection following successful DAA-based hepatitis C treatment

    We recommend that DAA-based treatment is made available for the treatment of  hepatitis C re-infection following successful DAA-based hepatitis C treatment.

    Solid Organ Transplantation

    HCV infection acquired from a donor organ can be readily treated with currently available drug regimens.  We recommend that patients without HCV infection should be offered an opportunity to receive an organ infected with HCV and we recommend that such recipients are offered antiviral therapy as soon as practicable post transplantation; with usual practice being to initiate treatment within the first month.

     Download PDF

    Friday, June 23, 2017

    Hepatitis C: AbbVies MAVIRET (glecaprevir/pibrentasvir) and Gilead’s Vosevi (Sofosbuvir/Velpatasvir/Voxilaprevir) Receives CHMP Positive Opinion

    AbbVies  MAVIRET (glecaprevir/pibrentasvir) and Gilead’s Vosevi (Sofosbuvir/Velpatasvir/Voxilaprevir) Receives CHMP Positive Opinion

    Two new medicines recommended for the treatment of chronic hepatitis C

    Maviret and Vosevi evaluated under accelerated assessment

    The European Medicines Agency has recommended granting marketing authorisations in the European Union (EU) for Maviret and Vosevi, two new medicines indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults.

    HCV infection is a major public health challenge. It affects between 0.4% and 3.5% of the population in different EU Member States and is the most common single cause of liver transplantation in the EU. Approximately 15 million people are chronically infected with HCV throughout Europe.

    Both Maviret and Vosevi are active against all genotypes of the virus and, with some differences between the two medicines, may be specifically useful in some patients who failed or cannot use previously available therapies. As this is considered to be of major public health interest in terms of therapeutic innovation, both medicines were evaluated under the EU’s accelerated assessment mechanism, which aims to speed up patients’ access to new medicines where there is an unmet medical need.

    Maviret and Vosevi belong to the direct acting antivirals against HCVs which have reshaped the way chronic HCV infection is treated. By blocking the action of proteins essential for HCV replication, this type of medicine achieves high cure rates of the infection and does not require the concomitant use of interferons, medicines which are associated with poor tolerability and potentially serious side effects.

    Despite the rapid development of new therapies there is still a need for a range of alternative treatment options to serve the different medical needs of the millions of people suffering from the disease. The more treatment options that are available, the better chance a patient has to get the right treatment to cure the disease and to lead a longer and healthier life.

    Maviret and Vosevi are the first medicines for which accelerated assessment has been carried out within 120 days, after a recent review of the timetable for this mechanism.

    Maviret contains two next generation direct-acting and antiviral agents: glecaprevir, an inhibitor of HCV NS3/4A protease, and pibrentasvir, an inhibitor of HCV NS5A. Both components are pangenotypic.

    The effects of Maviret were studied in a total of 2,376 patients who participated in eight pivotal and three supportive clinical trials. The hepatitis C virus could no longer be detected in over 90% of patients 12 weeks after the end of treatment. If the blood of patients is clear of hepatitis C virus for more than 12 weeks they are generally considered as being cured of the infection. Adverse events reported with Maviret were generally mild, including headache, fatigue, diarrhoea, nausea and abdominal pain.

    The applicant for Maviret received scientific advice from the Agency during the development of the medicine.

    Vosevi is composed of sofosbuvir (a nucleotide analogue non-structural protein NS5B polymerase inhibitor), velpatasvir (an HCV NS5A inhibitor), which were previously approved in other medicinal product, to which is added voxilaprevir (a novel pangenotypic HCV NS3/4A protease inhibitor).

    The effects of Vosevi were studied in four main clinical trials involving over 1,700 patients. Two studies were in previously untreated patients and two in patients in whom previous treatment (in some cases with an NS5A inhibitor) had not cleared the virus. Treatment was given for 12 weeks in the previously treated patients and eight weeks in the untreated. The hepatitis C virus could no longer be detected in over 90% of patients 12 weeks after the end of treatment with Vosevi. Mild nausea, headache and diarrhoea were the most common side effects observed. Other potentially related adverse effects were decreased appetite, vomiting, muscle spasms and rash.

    The opinions adopted by the CHMP at its June 2017 meeting are an intermediary step on Maviret's and Vosevi’s path to patient access. The CHMP opinions will now be sent to the European Commission for the adoption of decisions on EU-wide marketing authorisations through an accelerated procedure. Once a marketing authorisation has been granted, decisions about price and reimbursement will take place at the level of each Member State, taking into account the potential role/use of these medicines in the context of the national health system of that country.

    Notes
    The applicant for Maviret is AbbVie Ltd.
    The applicant for Vosevi is Gilead Sciences International Ltd.


    Press Release
    European CHMP Adopts Positive Opinion for Gilead’s Vosevi® (Sofosbuvir/Velpatasvir/Voxilaprevir) for the Treatment of All Chronic Hepatitis C Genotypes
    – Vosevi is Gilead’s Fourth Sofosbuvir-Based Treatment to Receive CHMP Positive Opinion for the Treatment of Chronic HCV Infection –
      
    FOSTER CITY, Calif.--(BUSINESS WIRE)--Jun. 23, 2017-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), has adopted a positive opinion on the company’s Marketing Authorization Application (MAA) for Vosevi®, an investigational, once-daily, single tablet regimen of sofosbuvir 400 mg, velpatasvir 100 mg, and voxilaprevir 100 mg (SOF/VEL/VOX) for the treatment of chronic hepatitis C virus (HCV)-infected patients. The data included in the application support the use of SOF/VEL/VOX in patients with and without compensated cirrhosis, with all genotypes (GT1-6) of HCV infection regardless of prior therapy, including 8 weeks of treatment for HCV direct-acting antiviral (DAA)-naïve patients without cirrhosis, as well as 12 weeks of treatment for patients who have previously failed therapy with a DAA-containing regimen.
      
    The CHMP positive opinion was adopted following an accelerated assessment procedure, reserved for medicinal products expected to be of major public health interest. The recommendation will now be reviewed by the European Commission, which has the authority to approve medicines for use in the 28 countries of the European Union, Norway and Iceland.
      
    The MAA for SOF/VEL/VOX is supported by data from four Phase 3 studies. Two studies (POLARIS-1 and POLARIS-4), evaluated 12 weeks of the single tablet regimen in patients with genotypes 1-6 HCV infection previously treated unsuccessfully with DAA-containing regimens, including NS5A inhibitors. Two other studies (POLARIS-2 and POLARIS-3) evaluated 8 weeks of SOF/VEL/VOX in DAA-naïve patients with genotypes 1-6 HCV infection. Across POLARIS-1 and POLARIS-4, 97 percent of patients treated with SOF/VEL/VOX (n=431/445) achieved the primary efficacy endpoint of SVR12. In POLARIS-2, 95 percent of patients with genotypes 1-6 HCV infection with and without cirrhosis treated with SOF/VEL/VOX (n=477/501) achieved the primary efficacy endpoint of SVR12. In POLARIS-3, 96 percent of patients with genotype 3 infection and cirrhosis treated with SOF/VEL/VOX (n=106/110) achieved the primary efficacy endpoint of SVR12. The most common adverse events among patients who received SOF/VEL/VOX in the POLARIS studies were headache, fatigue, diarrhea and nausea.
      
    Sofosbuvir as a single agent was granted marketing authorization in the European Union on January 16, 2014, under the trade name Sovaldi®, for use in combination with other agents. The single tablet regimen of sofosbuvir (400 mg) and ledipasvir (90 mg) received marketing authorization in the European Union on November 18, 2014, under the trade name Harvoni®. The single tablet regimen of sofosbuvir (400 mg) and velpatasvir (100 mg) received marketing authorization in the European Union on July 8, 2016, under the trade name Epclusa®.
      
    Gilead has also submitted a regulatory application for SOF/VEL/VOX in the United States. Gilead filed the New Drug Application for SOF/VEL/VOX on December 8, 2016, and the Food and Drug Administration (FDA) has set a target action date under the Prescription Drug User Fee Act of August 8, 2017.
      
    SOF/VEL/VOX is an investigational product and its safety and efficacy has not been established and is not approved anywhere globally.
    http://www.gilead.com/news/press-releases/2017/6/european-chmp-adopts-positive-opinion-for-gileads-vosevi-sofosbuvirvelpatasvirvoxilaprevir-for-the-treatment-of-all-chronic-hepatitis-c-genotypes

    Press Release
    AbbVie Receives CHMP Positive Opinion for MAVIRET™ (glecaprevir/pibrentasvir) for the Treatment of Chronic Hepatitis C in All Major Genotypes (GT1-6)
    - If approved, MAVIRET™ will provide a shorter, 8-week, pan-genotypic (GT1-6), once-daily option for the majority of people living with the hepatitis C virus (HCV)(1)*
    - MAVIRET would also be an additional HCV treatment option for patients with specific treatment challenges, such as those with compensated cirrhosis, chronic kidney disease and genotype 3
    - Final European Commission decision expected Q3 2017

    NORTH CHICAGO, Ill., June 23, 2017 /PRNewswire/ -- AbbVie ABBV 0.32%, a global biopharmaceutical company, today announced that the European Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has granted a positive opinion recommending marketing authorization of MAVIRET™ (glecaprevir/pibrentasvir), an investigational, pan-genotypic treatment for adults with chronic hepatitis C virus (HCV) infection. If approved, MAVIRET will be a once-daily, ribavirin-free, 8-week option for patients without cirrhosis and who are new to treatment across all genotypes (GT1-6), who comprise the majority of people living with HCV.1 The European Commission will now review the CHMP opinion and a final decision is expected in Q3 2017.

    "MAVIRET represents a new generation of HCV therapy and has the potential to be a shorter, 8-week option for patients living with this serious, chronic illness," said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. "Today's CHMP positive opinion takes us closer to delivering on AbbVie's mission to address continued unmet needs by bringing a new pan-genotypic option to people living with HCV in Europe."

    The CHMP positive opinion is supported by 97.5 percent (n=807/828) SVR12 rates with 8 weeks of MAVIRET across GT1-6 chronic HCV infected patients without cirrhosis and who are new to treatment, with varied patient and viral characteristics.2 In an integrated analysis (n=2,265), less than 0.4 percent of patients discontinued treatment.3 The reported adverse reactions (incidence greater than or equal to 10 percent) were headache and fatigue.3 The type and severity of adverse reactions in patients with cirrhosis were overall comparable to those seen in patients without cirrhosis.3

    "While the HCV treatment landscape has transformed significantly over recent years, the disease continues to be a global public health problem and treatment challenges remain," said Stefan Zeuzem, M.D., chief of the department of medicine at the J.W. Goethe University Hospital in Frankfurt, Germany. "In clinical studies, MAVIRET demonstrated high SVR rates across all genotypes of HCV patients (GT1-6). If approved, MAVIRET would remove many of the complexities of pre-treatment patient evaluation and has the potential to help facilitate the care and management of HCV."

    MAVIRET is also intended to be an additional option for patients with specific treatment challenges. This includes chronic HCV patients with compensated cirrhosis (Child-Pugh A), and those who currently have limited treatment options, such as patients with severe chronic kidney disease, including those on dialysis, and patients infected with genotype 3.

    The marketing authorization application (MAA) for MAVIRET is under an accelerated assessment by the EMA, which is granted to new medicines of major public health interest. The MAA evaluation is conducted under the centralized licensing procedure, and if approved, will result in a marketing authorization valid in all 28 member states of the European Union, as well as Iceland, Liechtenstein and Norway. AbbVie's investigational, pan-genotypic regimen has also been granted accelerated review designations by other regulatory authorities including the U.S. Food and Drug Administration and Japanese Ministry of Health, Labour and Welfare. MAVIRET is an investigational regimen and its safety and efficacy have not been established. 

    About MAVIRET™ (glecaprevir/pibrentasvir)
    AbbVie's MAVIRET™ (glecaprevir/pibrentasvir) clinical development program was designed to investigate a pan-genotypic, once-daily, ribavirin-free treatment with the potential to provide a faster path to virologic cure** for all major HCV genotypes (GT1-6) and with the goal of addressing specific treatment challenges, including compensated cirrhosis (Child-Pugh A), chronic kidney disease and genotype 3. MAVIRET is being evaluated as a potential 8-week, pan-genotypic treatment for the majority of people living with HCV,1 those without cirrhosis and who are new to treatment,* and regardless of viral and patient characteristics.

    MAVIRET is a fixed-dose combination of two distinct antiviral agents: glecaprevir (100mg), an NS3/4A protease inhibitor, and pibrentasvir (40mg), an NS5A inhibitor, dosed once-daily as three oral tablets.

    Glecaprevir was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals ENTA 1.16% for HCV protease inhibitors and regimens that include protease inhibitors.

    *Patients who are treatment-naive or had prior treatment experience with IFN-based treatments ([peg]IFN +/- RBV or SOF/RBV +/- pegIFN).
    **Patients who achieve a sustained virologic response at 12 weeks post treatment (SVR12) are considered cured of hepatitis C. 
    http://www.prnewswire.com/news-releases/abbvie-receives-chmp-positive-opinion-for-maviret-glecaprevirpibrentasvir-for-the-treatment-of-chronic-hepatitis-c-in-all-major-genotypes-gt1-6-630334863.html